I started my clinical research career as a Clinical Research Coordinator (CRC) at a hospital site, recruiting patients and coordinating drug trials. After 3 years at the hospital site, I transitioned into a Clinical Research Associate (CRA) role at an in-vitro diagnostic sponsor company, working on in-vitro diagnostic test, biologic products, and 510(k) automated instrumentation. From there I progressed into my current role in drug trial management, overseeing clinical development at a non-profit drug company. Below are summary of what I know about drug development.
Drug development involve multiple stages. The process from start to finish can take lots of funding and time (many years). Large drug companies usually have multiple drug candidates that go through the development process at the same time. Out of the many, only a few will make it to regulatory approval and be sold to the public. This is the reason why new drug costs so much. The cost is to support this lengthy and costly process of drug development.
The process of drug development includes:
- Drug Discovery
- Pre-clinical testing
- Clinical trials
- Post market surveillance
Drug discovery is the process that new drug candidates are screened and selected. Thousands of potential small molecules, natural products, or extract are initially screened for desired therapeutic effects. For example, candidates for protease inhibitor should bind the protein protease with certain affinity, selectivity, potency, and metabolic stability. Oral stability and bioavailability should also be considered for the candidates to be made into a pill that can be swallowed. Once one or more top candidates are selected, the next step is to conduct pre-clinical testing to confirm safety, toxicity, pharmacokinetics and metabolism.
Prior to testing new drug candidate on human, extensive pre-clinical testing in animals must be done to ensure the safety of the new drug. Pre-clinical testing is also conducted to learn of any toxicity, metabolism profile, and pharmacokinetic of the new drug. Pharmacokinetic studies, commonly referred as PK studies, are conducted to learn what happens to the new drug in a living organism, from the moment it enters the body to the moment it get eliminated through urine and stool. Pre-clinical testing also includes studying the biochemical and physiological effects of the drug on the body. This is called Pharmacodynamics or PD studies. PD studies aim to learn the mechanisms of drug action and the impact of drug concentration on the living organism. From PK and PD studies, appropriate doses and dosing schemes of the new drug can be determined.
The chemical makeup of the new drug is also studied in pre-clinical testing. This includes the solubility, stability, and formulation of the new drug in different forms (capsules, tablets, aerosol, injectable, and intravenous). This portion of chemical studies is known as Chemistry, Manufacturing and Control (CMC).
In addition, other studies may include genotoxicity, carcinogenicity, and reproduction toxicity.
Once extensive pre-clinical testing showed promising results for the new drug candidate, the next step is to conduct clinical trial in human. In United States, prior to conducting clinical trial in human, an application to the FDA called Investigational New Drug (IND) application. Below is a link for FDA 21 CFR 312, the regulation that govern new drug candidate that requires IND. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312
If the sponsor or drug manufacturer does not receive any objection notice from the FDA within 30 days after IND application submission and the clinical trial has been approved by the IRB, the clinical trial can start.
Clinical trials in human are often done in phases:
Phase 0 – Pharmacokinetics (PK) and Pharmacodynamics (PD)
This is first in human trial where pharmacokinetics (PK) and pharmacodynamics (PD) are studies. The number of subjects are usually very small (N = 10 to 15)
– Pharmacokinetics (PK) studies are done similar to the PK studies described in pre-clinical testing to understand what happens to the new drug from the moment it under human body to excretion. PK studies are done to learn what the body does to the new drug.
– Pharmacodynamics (PD) studies are opposite to the PK studies. PD studies are done to learn what the new drug does to the body.
NOTE: Phase 0 is commonly described as part of Phase I below.
Phase I – Safety
Phase I studies are often done in small number (N = 20 – 80) of healthy subject. The goal of this phase is to learn of the safety of the new drug. To avoid further complication and symptoms from underlining disease, healthy subjects are recruited into this phase. Exception to this includes oncology trials where actual disease patient may be used. Phase I studies are often done in a specialized facility or clinic where continuous monitoring of subjects can be done. These facilities or clinics are often called CPUs (Central Pharmacological Units). Side effects of the new drug are carefully recorded in phase I studies. In addition, phase I studies are often designed to test single (Single Ascending Dose) and multiple (Multiple Ascending Dose) dosage and dosing interval to learn of the range where the new drug is safe in human.
Phase II – Efficacy (Proof of Concept)
Phase II studies are done in larger number of subjects (N = 100 – 200). The population for this phase is patient with the disease where the new drug is intended to treat. Study design for phase II studies usually compares the new drug against standard care treatment and / or placebo group. Placebo is an inert substance that has no medical effect (e.g. sugar pill). The goal of phase II studies is to test for efficacy of the new drug. Additional safety information is also usually collected. Phase II studies can be done in two stages, phase IIa to compared dosing and dose regiment and phase IIb to evaluate efficacy and safety. Sometimes, phase I and phase II are done in combination to evaluate efficacy and toxicity in order to save time and cost. Since phase II studies evaluate efficacy, this phase can be referred as “Proof of Concept.” Phase II usually determine the fate of the new drug; continue to phase III if shown efficacy vs. discontinue clinical testing if shown ineffective.
Phase III – Pivotal Studies
Phase III studies are designed to obtain large enough population to show statistical evidence of efficacy and safety of the new drug. Phase III studies are often done in large number of patients with the disease the new drug is intended to treat (N = 300 – 3000). Similar to phase II, new drug in phase III studies are being compared against standard care treatment and / or placebo group. Due to the large number of patients being evaluated, phase III studies are time consuming and costly. Similar to phase II, phase III studies can be done in stages; phase IIIa to evaluate efficacy and safety and phase IIIb to evaluate additional disease indication or additional marketing claims. Due to the evaluation of efficacy and safety in large population, phase IIIa are often called “Pivotal Study.” While not required in all cases, often 2 successful phase IIIa trials are needed to show efficacy and safety to obtain regulatory approval from major regulatory bodies such as the FDA in the U.S. and EMA in European Union. Upon favorable results from these phase IIIa trials, sponsor or drug manufacturer may submit a New Drug Application (NDA) to the FDA or EMA for regulatory approval.
Phase IV – Post Marketing Surveillance
Phase IV studies are usually done after regulatory approval of the new drug. The goal of phase IV studies is to collect safety information in larger population (general population) and in longer time period (multiple years) than in phase I, II, and III trials. Phase IV studies are necessary to protect patient’s safety after regulatory approval of new drug. As safety information are collected and reported to the overseeing regulatory body, if serious side effects are found, the new drug may be restricted to certain use or it may be prohibited from being sold altogether.
Picture Credit: Pills, by mattza, flickr